Xuebijing Injection Maintains GRP78 Expression to Prevent Candida albicans-Induced Epithelial Death in the Kidney.

Ting Shang,Xin-Tong Wang,Qilin Yu,Xiumei Gao,Hongyan Zhu,Jia-Ming Gao,Tongtong Ren,Ming-Chun Li,Yan Zhu,Guixiang Pan,Yuxin Feng

doi:10.3389/fphar.2019.01416

Ting Shang, Xin-Tong Wang + Show 9 more

Open Access

https://doi.org/10.3389/fphar.2019.01416

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Abstract

Sepsis and septic shock threaten the survival of millions of patients in the intensive care unit. Secondary fungal infections significantly increased the risk of mortality in sepsis patients. Chinese medicine Xuebijing injection (XBJ) has been routinely used as an add-on treatment to sepsis and septic shock in China. Our network pharmacology analysis predicted that XBJ also influences fungal infection, consisting with results of pioneer clinical studies. We conducted in vivo and in vitro experiments to verify this prediction. To our surprise, XBJ rescued mice from lethal Candida sepsis in a disseminated Candida albicans infection model and abolished the colonization of C. albicans in kidneys. Although XBJ did not inhibit the growth and the virulence of C. albicans in vitro, it enhanced the viability of 293T cells upon C. albicans insults. Further RNA-seq analysis revealed that XBJ activated the endoplasmic reticulum (ER) stress pathway upon C. albicans infection. Western blot confirmed that XBJ maintained the expression of GRP78 in the presence of C. albicans. Interestingly, key active ingredients in XBJ (C0127) mirrored the effects of XBJ. C0127 not only rescued mice from lethal Candida sepsis and prevented the colonization of C. albicans in kidneys, but also sustained the survival of kidney epithelial cells partially by maintaining the expression of GRP78. These results suggested that XBJ may prevent fungal infection in sepsis patients. Pre-activation of ER stress pathway is a novel strategy to control C. albicans infection. Network pharmacology may accelerate drug development in the field of infectious diseases.

Highlights

Fungal infection causes an annual mortality of 1.5 million people worldwide (Wirnsberger et al, 2016)
We revealed that XBJ may regulate GRP78 to improve the survival of kidney epithelial cells upon C. albicans insult and the combination of four compounds in XBJ can maintain GRP78 expression
Our results showed that combining both methods provides advantages to advance medicine

Summary

Introduction

Fungal infection causes an annual mortality of 1.5 million people worldwide (Wirnsberger et al, 2016). The cost of treating invasive fungal infection is over 2 billion dollars in the US (Pfaller and Diekema, 2010). As the leading pathogen in patients suffering invasive fungal infections, Candida albicans fostered 50% of candida sepsis cases (Pfaller and Diekema, 2010; Brown et al, 2012). Limited choices of antifungal drugs are available to treat fungal infections with only two non-toxic antifungal classes for candidiasis (Diekema et al, 2012). Invasive C. albicans infection still claims mortality of 45% to 75% (Brown et al, 2012). Emerging drugresistant fungal infections are calling for novel management strategies to restrain fungal sepsis (Healey et al, 2016)

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